Mitigation of thromboinflammation by rivaroxaban ameliorates metabolic and structural manifestations of metabolic dysfunction-associated steatohepatitis in rats: Comparison to other antithrombotic drugs.

Metabolic dysfunction-associated steatohepatitis (MASH) poses a significant public health challenge, characterized by liver fat accumulation accompanied with inflammation and cell damage. Patients with MASH commonly exhibit hypercoagulability. Our previous work showed that direct oral anticoagulants exert anti-inflammatory effects in early stages of metabolic dysfunction. Mitigation of thromboinflammation ameliorated the manifestations of cardiometabolic complications. Here, we examine the protective effects of rivaroxaban in a rat model of MASH and compare it to representatives of 2 other antithrombotic drug classes, enoxaparin and clopidogrel, as well as silymarin, a bona fide hepatoprotective agent. Rats were divided into 6 groups: control, MASH (induced by an atherogenic diet), and treatment groups receiving either silymarin (50 mg/kg by mouth), rivaroxaban (20 mg/kg by mouth), enoxaparin (2 mg/kg subcutaneously), or clopidogrel (6.75 mg/kg by mouth) for 8 weeks, starting in the third week of induction. MASH rats showed elevated markers of visceral adipose thromboinflammation, along with liver injury markers (aspartate aminotransferase, alanine aminotransferase, and serum albumin), heightened hepatic levels of inflammatory cytokines (interleukin [IL]-1β and IL-6), reduced antioxidant capacity, and an imbalance in coagulation factors (elevated activated coagulation Factor X and Factor VIII/Protein C) compared with the control group. Anticoagulants and silymarin treatment led to varying degrees of amelioration of these MASH-associated abnormalities. Rivaroxaban demonstrated the most substantial improvement in thromboinflammatory markers, reaching levels comparable to the control group, with percentage improvements of approximately 52%, 49%, and 42% in activated coagulation Factor X, IL-1β, and IL-6, respectively. These findings suggest that direct oral anticoagulants hold promise as therapeutic agents for MASH by targeting the underlying thromboinflammatory state. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatohepatitis is a global health issue. In a rat model of the disease, rivaroxaban improves liver injury markers, outperforming bona fide hepatoprotective substances. This study emphasizes the role of thromboinflammation in metabolic dysfunction-associated steatohepatitis and highlights direct anticoagulants as a potential novel treatment approach.